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Abstract:

A method for preparing a halofuginone derivative, in particular a method
for preparing an inhibitor medicament expressed by specific I-type
procollagen in the invention a condensate of formula (II) reacts for
12-35 hours in a catalytic hydrogenation solvent with the existence of
Ni--B amorphous alloy catalyst, at the hydrogen pressure of 0.1-10 Mpa
and at the temperature of 10-60° C., and then the catalyst is
filtered, the filtrate is decompressed to recover the solvent, the pH
value is regulated to obtain a crude product of formula (I), and the
crude product of the formula (I) is refined to obtain a refined product
of formula (I).

Claims:

1. A preparation method of halofuginone derivative with features of the
following steps: (1) The condensate shown in formula (II) is a raw
material, which reacts for 12-35 hours in catalytic hydrogenation solvent
under 10.about.60.degree. C. and 0.1.about.1.0 MPa controlled hydrogen
pressure, with presence of and Ni--B non-crystalline alloy catalyst, as
shown in the following formula: ##STR00006## wherein the aforementioned
Ni--B non-crystalline alloy catalyst is prepared by loading Ni--B
non-crystalline alloy on aluminium oxide or zeolite carrier, with a load
of 1.0.about.20.0% (as weight percentage); wherein the weight ratio
between the Ni--B non-crystalline alloy catalyst and condensate (II) is
1:10.about.40; wherein the catalytic hydrogenation solvent is
0.1.about.0.6N acidic aqueous alcohol solution containing a mass of
catalytic hydrogenation solvent being 8-20 times that of the condensate
(II); wherein the Ni--B non-crystalline alloy catalyst is prepared as
follows: add nickel salt into the aqueous solvent until it is dissolved;
then add carrier, such as aluminium oxide or zeolite; KBH4 solution
should be added drip by drip under 0.about.30.degree. C.; after reaction
over, filter the solution, wash the precipitates with deionized water
until pH reaches 6.5.about.7.5, and finally store the treated
precipitates in anhydrous ethanol for use; the nickel salt above is
optional among Ni(NO3)2, NiCl2 or Ni(SO4)2; (2) Filter the catalyst and
treat the yielded filtrate appropriately before obtaining
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative (I) crude; (3) Through refining procedures, obtain the refined
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative (I) from the crude; wherein the refining procedures are as
follows: add the
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative crude to the re-crystallizing solvent for reflux for more than
8 h, then decolorise it with activated carbon and crystallize it under
0.about.40.degree. C. for 3-8 h; finally the refined product can be
obtained; wherein the selected re-crystallizing solvent is a mixed
solution of alcohol, water and halohydrocarbon. The mixed solvent
requires 5-15 times the
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative crude in weight; wherein the ratio of the mixed solvent for
the re-crystallization is: the mass ratio of
alcohol:water:halohydrocarbon=1:0.1.about.0.3:0.05.about.0.2; wherein the
Alcohol used in the solvent for the re-crystallization is C1.about.C4
alcohol; wherein the Halohydrocarbon used in the solvent for the
re-crystallization is optional among dichromethane, trichloromethane,
dichroethane or carbon tetrachloride.

2. In accordance with the preparation method described in claim 1, its
feature is the said catalyst is Ni--B non-crystalline alloy catalyst
prepared by loading Ni--B non-crystalline alloy on aluminium oxide or
zeolite carrier, with a load of 1.0.about.10.0%.

3. In accordance with the preparation method described in claim 1, its
feature is the mass ratio between the said Ni--B non-crystalline alloy
catalyst and condensate (II) is 1:10.about.20.

4. In accordance with the preparation method described in claim 1, its
feature is the number of re-using the said Ni--B non-crystalline alloy on
aluminium oxide or zeolite carrier for 5-10 times.

5. In accordance with the preparation method described in claim 1, its
feature is the mass required for the catalytic hydrogenation solvent is
8-15 times that of the condensate (II).

6. In accordance with the preparation method described in claim 1, its
feature is the acid used in the said catalytic hydrogenation solvent is
optional among H2SO4, hydrochloric acid, formic acid or acetate.

7. In accordance with the preparation method described in claim 1, its
feature is the said catalytic hydrogenation solvent is 0.1.about.0.4N
acidic aqueous alcohol solvent, and the alcohol is optional among
methanol, ethanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol
or amyl alcohol; wherein the mass of water contained in the said aqueous
alcohol solvent is 5.about.30% that of the alcohol.

8. In accordance with the preparation method described in claim 1, its
feature is the hydrogen pressure during catalytic hydrogenation is
0.1.about.0.6 Mpa and the catalytic hydrogenation temperature is
10.about.60.degree. C.

9. In accordance with the preparation method described in claim 1, its
feature is the said catalytic hydrogenation time is 15-25 hours.

10. In accordance with the preparation method described in claim 1, its
feature is the ratio among nickel salt, carrier and KBH4 during step (1),
the preparation process of the Ni--B non-crystalline alloy catalyst, is
0.02.about.1.0:0.8.about.1.2:1.0 (in mol), and the temperature for
reduction reaction is 0.about.10.degree. C.

11. In accordance with the preparation method described in claim 1, its
feature is the selected re-crystallizing solvent as described in step (3)
is a mixed solution of alcohol, water and halohydrocarbon, and this
mixture requires 5-10 times
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative crude in weight.

12. In accordance with the preparation method described in claim 1, its
feature is the alcohol used in the re-crystallizing solvent as described
in step (3) is optional among methanol, ethanol, isopropyl alcohol or
propyl alcohol.

13. In accordance with the preparation method described in claim 1, its
feature is the crystallization temperature as described in step (3) is
0.about.15.degree. C.; The crystallization time is 3-5 hours.

Description:

TECHNICAL FIELD

[0001] The present invention involves with a chemical preparation method,
specifically a preparation method of an inhibitor of specific collagen
type I gene expression.

TECHNICAL BACKGROUND

[0002] According to WHO reports, malaria is the most serious known
infectious disease, with incidence of 300-600 million cases per year
globally and mortablity of 3 million, particularly common among African
infants and other vulnerable populations. Although existing drugs such as
quinoline, chloroquine, etc have some effects on malaria, the human body
will rapidly generate resistance during treatments. Nevertheless, ancient
Chinese people used the Saxifragaceae herb Dichroa febrifuga (Chang Shan)
to cure malaria. In 1950s, Chinese scientists extracted febrifugine from
the plant and discovered its anti-malarial activity. The absolute
configuration of its compound, however, was not finally determined until
1999 through chiral synthesis.

[0003] Halofuginone derivative, as an inhibitor of specific type I
collagen gene expression, may play a role in many fiber cells and inhibit
collagen expression synthesis in experimental fibrosis models of liver,
lung, derma and uterus. The most important halofuginone derivatives are
Halofuginone and Febrifugine. As Halofuginone plays a role in specific
collagen transcription, it is a promising anti-hepatic fibrosis agent. In
2002, Tempostatin® (Halofuginone hydrobromide) developed by Collgard
Biopharms was approved in Europe as a new orphan drug for treatment of
systemic sclerosis. RU-19110 developed by a French company, Roussel Ucla,
has entered clinical study.

[0004] Currently, synthesis of halofuginone derivatives generally refers
to procedures developed by Japanese scientist Takeuchi Y (Chemical
Communication, 2000, 1643-1644), which applies enzyme reduction to get
key chiral intermediate, then obtain bromide A via a four-step reaction,
and finally obtain CBZ-protected halofuginone derivative
(3-)[[(3aR,7aS)-N-CBZ-2-hydroxyl-Octahydro furan and
[3,2-b]2-Piperidinyl]methyl]-4(3H)-quinazolinone) through condensation
(as shown in structural formula II). In his method, deprotection is
performed as palladium hydroxide-catalyzed hydrogenation. The method
includes 11 steps, with a total yield of 5.88%. However, side reactions
will occur when using palladium hydroxide-catalyzed hydrogenation as
deprotection, e.g., carbon-nitrogen double bond in the quinazolinone
structure will be reduced additively to produce by-products such as C1;
if quinazolinone structure contains bromine and chlorine, it is easier to
be deprotected to produce by-products such as C2 and C3. Therefore, this
method is not applicable to commercial production of Halofuginone.

##STR00001##

[0005] Haruhisa K et al. also reported that palladium on carbon catalytic
hydrogenation process is not applicable to some halofuginone derivatives,
and acid reflux method for deprotection is not applicable to condensate
(II) as hydroxyl in the condensate structure is easy to be removed (J.
Med. Chem., 2006, 49, 4698). Only hydroxyl in the condensate structure
firstly protected can then strong acid reflux method to be used in
deprotection (U.S. Pat. No. 6,420,372).

##STR00002##

[0006] Kobayashi S. reported a method which uses chiral formaldehyde as
raw material to obtain hydroxyl-protected piperidine bromide B via
synthesis, followed by condensation to obtain hydroxyl-protected
condensate V, then use palladium on carbon catalytic hydrogenation and
acid, respectively, to deprotect CBZ and R1 (U.S. Pat. No. 6,420,372
and J. Org. Chem., 1999, 64, 6833). The process uses expensive catalyst
to synthesize hydroxyl-protected piperidine bromide B but with low yield,
so the process is only applicable to lab-scale preparation of
halofuginone derivative rather than commercial production.

##STR00003##

[0007] Chinese Patent No. ZL200410045471 and Taniguchi T. et al. (Org.
Lett., 2000, 2, 3193) reported that take epoxy compound C of piperidine
structure as a key intermediate, condense it with quinolinone, obtain
condensate V via Dess-Martin oxidation, and then obtain halofuginone
derivative after deprotection by hydrogenation or acid. This method not
only needs 10 steps to obtain epoxy compound 3, but also needs rare metal
with a total yield of 11%. Furthermore, the application of RCM reaction
and rare metal limits its commercial use.

##STR00004##

[0008] Therefore, developing an effective and simple method to deprotect
CBZ in condensate (II) is key to synthesize halofuginone via chemical
methods. The present invention for the first time proposes Ni--B
non-crystalline alloy as catalyst to deprotect CBZ via catalytic
hydrogenation.

Invention Content

[0009] The present invention develops a production method with higher
efficiency and simpler process to overcome current technical
deficiencies.

[0010] The present invention adopts the following technical solution, i.e.
a preparation method of
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative as shown in formula (I). This solution includes steps as
follows: Condensate shown in formula (II) fully reacts in the catalytic
hydrogenation solvent under 0.1˜1.0 MPa controlled hydrogen
pressure and 10˜60° C., with presence of Ni--B
non-crystalline alloy catalyst; then filter the catalyst, reduce pressure
on the yielded filtrate to recover the solvent, and add 300 ml water to
adjust pH value within 9˜10; then obtain
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative (I) crude which can be further refined to be refined form. The
said Ni--B non-crystalline alloy catalyst is prepared by loading Ni--B
non-crystalline alloy on aluminium oxide or zeolite carrier, with a load
of 1.0˜20.0%, the mass ratio between the said Ni--B non-crystalling
alloy catalyst and condensate (II) is 1:10˜40; the said catalytic
hydrogenation solvent is 0.1˜0.4N acidic aqueous alcohol solution.

Detailed steps, as well as features, are as follows: (1) The condensate
shown in formula (II) is a raw material, which fully reacts for 12-35
hours in the catalytic hydrogenation solvent with the presence of Ni--B
non-crystalline alloy catalyst, under conditions of 0.1˜1.0 MPa
controlled hydrogen pressure and temperature of 10˜60° C.
This catalytic hydrogenation time, 12-35 hours, may depend on raw
material reaction status which need to be traced by liquid
chromatography. A complete reaction is shown as the following formula:

##STR00005##

Through the above-mentioned hydrogenation process, double bond reduction
product C3 and dehalogenated products C1 and C2 can be obtained with low
contents along with crude product. The yielded crude can be further
refined to get high purity product
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative.

[0011] The said Ni--B noncrystalline alloy catalyst is prepared by loading
Ni--B non-crystalline alloy on aluminium oxide or zeolite carrier, with a
load of 1.0˜20.0% (as weight percentage);

[0012] The mass ratio between the Ni--B non-crystalline alloy catalyst and
condensate (II) is 1:10˜40;

[0013] The catalytic hydrogenation solvent is 0.1˜0.4N acidic
aqueous alcohol solution and the mass required of which is 8-20 times
that of the condensate (II);

[0014] The Ni--B non-crystalline alloy catalyst is prepared as follows:
add nickel salt into the aqueous solvent until it is dissolved; then add
carrier, such as aluminium oxide or zeolite; KBH4 solution should be
added drip by drip under 0˜30° C.; after reaction over,
filter the solution, wash the precipitates with deionized water until pH
value reaches 6.5˜7.5, and finally store the treated precipitates
in anhydrous ethanol for use; the nickel salt above is optional among
Ni(NO3)2, NiCl2 or Ni(SO4)2;

[0015] The refining procedures are as follows: add the
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative crude to the re-crystallizing solvent for reflux for more than
8 hours, then decolorise it with activated carbon and crystallize it
under 0˜40° C. for 3-8 hours; finally the refined product
can be obtained;

[0016] The selected re-crystallizing solvent is a mixed solution of
alcohol, water and halohydrocarbon. The mixed solvent requires 5-15 times
of the 3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazo-
linone derivative crude in weight;

[0017] The ratio of the mixed solvent for the re-crystallization is: the
mass ratio of
alcohol:water:halohydrocarbon=1:0.1˜0.3:0.05˜0.2:Alcohol used
in the solvent for the re-crystallization is C1˜C4 alcohol;

[0018] Halohydrocarbon used in the solvent for the re-crystallization is
optional among dichromethane, trichloromethane, dichroethane or carbon
tetrachloride.

[0019] Preferably in the preparation method of the present invention, the
said catalyst is Ni--B non-crystalline alloy catalyst prepared by loading
Ni--B non-crystalline alloy on aluminium oxide or zeolite carrier, with a
load of 1.0˜10.0%.

[0020] Preferably in the preparation method of the present invention, the
mass ratio between the said Ni--B non-crystalline alloy catalyst and
condensate (II) is 1:10˜20.

[0021] Preferably in the preparation method of the present invention, the
number of re-using the said Ni--B non-crystalline alloy on aluminium
oxide or zeolite carrier is 5-10 times.

[0022] Preferably in the preparation method of the present invention, the
mass required for the catalytic hydrogenation solvent is 8-15 times that
of the condensate (II).

[0023] Preferably in the preparation method of the present invention, the
acid used in the said catalytic hydrogenation solvent is optional among
H2SO4, hydrochloric acid, formic acid or acetate.

[0024] Preferably in the preparation method of the present invention, the
said catalytic hydrogenation solvent is 0.4N acidic aqueous alcohol
solvent, and the alcohol is optional among methanol, ethanol, isopropyl
alcohol, n-butanol, isobutanol, tert-butanol or amyl alcohol;

[0025] The mass of water contained in the said aqueous alcohol solvent is
5˜30% that of the alcohol.

[0026] Preferably in the preparation method of the present invention, the
hydrogen pressure during catalytic hydrogenation is 0.1˜0.6 Mpa and
the catalytic hydrogenation temperature is 10˜60° C.

[0027] Preferably in the preparation method of the present invention, the
said catalytic hydrogenation time is 15-25 hours.

[0028] Preferably in the preparation method of the present invention, the
ratio among nickel salt, carrier and KBH4 during step (2), the
preparation process of the Ni--B non-crystalline alloy catalyst, is
0.02˜1.0:0.8˜1.2:1.0 (in mol), and the temperature for
reduction reaction is 0˜10° C.

[0029] Preferably in the preparation method of the present invention, the
selected re-crystallizing solvent as described in step (3) is a mixed
solution of alcohol, water and halohydrocarbon, and this mixture requires
5-10 times of
3-[3-[(2R,3S)-3-hydroxyl-2-piperidinyl]-2-oxypropyl]-4(3H)-quinazolinone
derivative crude in weight.

[0030] Preferably in the preparation method of the present invention, the
alcohol used in the re-crystallizing solvent as described in step (3) is
optional among methanol, ethanol isopropyl alcohol or propyl alcohol.

[0031] Preferably in the preparation method of the present invention, the
crystallization temperature as described in step (3) is
0˜15° C.; the crystallization time is 3-5 hours.

[0032] Compared with existing technologies, the present invention has
benefits as follows:

(1) The Ni--B non-crystalline alloy catalyst carried on aluminium oxide
or zeolite applied in the present invention can be reused without losing
activity. Catalytic hydrogenation under common or reduced pressure can
inhibit the generation of by-products and therefore substantially
improves the reaction selectivity. (2) The present invention provides a
simple refining method which improves product quality and can be applied
to large-scale commercial production.

SPECIFIC OPERATIONS

[0033] The following details the preparation of the Ni--B non-crystalline
alloy catalyst with examples:

Example 1

[0034] Add 0.67 mol of Ni(NO3)2 into a four-neck flask, add 100
g aluminium oxide, then add 1.0 mol of KBH4 solution drip by drip
while stirring in 0° C. When the drip feed ends, keep it in
reaction until no gas is released, then stop the reaction. Filter it,
repeatedly wash the black precipitate with deionized water until pH=7,
then wash it for four times with anhydrous ethanol and finally store it
in anhydrous ethanol for use.

Example 2

[0035] Add 0.33 mol of Ni(NO3)2 to a four-neck flask, and add
100 g zeolite, add 1.0 mol of KBH4 solution drip by drip while
stirring in 10° C. When the drip feed ends, keep it in reaction
until no gas is released, then stop the reaction. Filter it, repeatedly
wash the black precipitate with deionized water until pH=7.2, then wash
it for six times with anhydrous ethanol and finally store it in anhydrous
ethanol for use.

Example 3

[0036] Add 0.033 mol of Ni(NO3)2 into a four-neck flask, add 100
g aluminium oxide, then add 1.0 mol of KBH4 solution drip by drip
while stirring in 10° C. When the drip feed ends, keep it in
reaction until no gas is released, then stop the reaction. Filter it,
repeatedly wash the black precipitate with deionized water until pH=7.4,
then wash it for eight times with anhydrous ethanol and finally store it
in anhydrous ethanol for use.

Example 4

[0037] Add 0.1 mol of Ni(NO3)2 into a four-neck flask, add 100 g
zeolite, then add 1.0 mol of KBH4 solution drip by drip while
stirring in 30° C. When the drip feed ends, keep it in reaction
until no gas is released, then stop the reaction. Filter it, repeatedly
wash the black precipitate with deionized water until pH=6.5, then wash
it for six times with anhydrous ethanol and finally store it in anhydrous
ethanol for use.

Example 5

[0038] Add 0.5 mol of Ni(NO3)2 into a four-neck flask, add 100 g
aluminium oxide, then add 1.0 mol of KBH4, solution drip by drip
while stirring in 10° C. When the drip feed ends, keep it in
reaction until no gas is released, then stop the reaction. Filter it,
repeatedly wash the black precipitate with deionized water until pH=6.8,
then wash it for nine times with anhydrous ethanol and finally store it
in anhydrous ethanol for use.